番茄社区

A single subcutaneous injection of an investigational monoclonal antibody was safe and effective in preventing malaria in children in Mali, according to results of the phase II Mali Malaria mAB trial.

Among 225 children ages 6 to 10 years, 48% of those who received a 150-mg dose of the monoclonal antibody L9LS and 40% who received a 300-mg dose became infected with Plasmodium falciparum compared with 81% of those who received placebo, which translated into an efficacy of 66% and 70% for the two doses, respectively, compared with placebo (P<0.001 for both), reported Peter Crompton, MD, MPH, of the National Institute of Allergy and Infectious Diseases, and colleagues.

In addition, 28% of kids in the 150-mg group, 19% in the 300-mg group, and 59% in the placebo group developed clinical malaria. Efficacy against clinical malaria was 67% with the lower dose and 77% with the higher dose compared with placebo (P<0.001 for both), they noted in the .

Importantly, no safety concerns were identified, Crompton and team said.

"There is an urgent need for long-acting drugs that can be delivered through a single healthcare contact to provide immediate high-level protection against malaria in high-risk populations, and this study demonstrates that this is an achievable goal," Crompton told 番茄社区 in an email.

According to the WHO, P. falciparum caused in 2022, most of which occurred among young children in Africa.

"We in the global malaria community are at a critical juncture in our journey toward malaria eradication," wrote Trevor Mundel, MD, PhD, of the Bill and Melinda Gates Foundation in Seattle, in . "Decades of experience in deploying our existing interventions have made it clear that there is no single 'silver bullet.'"

L9LS is a monoclonal antibody with an extended half-life that targets a conserved junctional epitope on the P. falciparum circumsporozoite protein. The pharmacokinetics and safety of L9LS were initially evaluated in a U.S.-based phase I trial. This early trial of L9LS also showed that it protected adults exposed to malaria in a controlled environment.

Previously, another single-dose monoclonal antibody CIS43LS that targeted the same epitope demonstrated efficacy against malarial infection in a phase II trial. However, CIS43LS required intravenous administration, potentially hindering widescale administration.

"Anti-malarial monoclonal antibodies with extended half-lives are promising new tools to combat the ancient scourge of malaria," Crompton said. "Innovative approaches will be required to make anti-malarial monoclonal antibodies affordable in Africa, and I'm optimistic that studies like this will catalyze public-private partnerships that make that goal a reality."

Current prevention strategies, such as seasonal malaria chemoprevention in children and even the newer malaria vaccines (RTS,S/AS01 and R21/Matrix-M), are plagued by obstacles, including delivery, need for multiple interactions with healthcare systems, and adherence, Mundel commented in the editorial.

"A monoclonal antibody or long-acting injectable drug that can deliver safe and cost-effective preventive efficacy from a single dose with a long duration of protection ... would address these limitations," he wrote. "These new product classes ... could conceivably be more feasible and effective prophylactic measures than either seasonal malaria chemoprevention or the currently recommended malaria vaccines."

Despite the promising results of the trial, "improvements in both potency and pharmacokinetics are likely to be needed in order for monoclonal antibodies to have a broad effect in reducing the malaria burden," Mundel posited. "Trials that not only provide clinical insight but also show operational feasibility and the potential for cost-effective scale would provide a compelling argument for the acceleration of development and prequalification of this new class of product."

The was conducted in two phases. Part A assessed safety of L9LS first in 18 adults at three dose levels and then among a total of 36 children at two dose levels. In part B, 225 children were randomized 1:1:1 to receive 150-mg L9LS, 300-mg L9LS, or placebo.

All participants were treated with the antimalarial agent artemether-lumefantrine (Coartem) before administration of L9LS or placebo to clear possible P. falciparum infection. Any asymptomatic P. falciparum infections were not treated for the remainder of the trial.

Enrolled children ages 6 to 10 years received the injections of L9LS before the peak of the malaria season in Mali, which runs from July through December. The primary efficacy endpoint of the trial was blood-stage infection with P. falciparum, regardless of the presence of clinical symptoms.

The secondary endpoint was clinical malaria, defined as a body temperature of at least 37.5°C or a history of fever in the previous 24 hours and P. falciparum asexual parasitemia of more than 5,000 parasites/mm³, or an illness accompanied by any level of parasitemia that led to receipt of antimalarial treatment.

No serious adverse events were reported among adults in part A of the study, and all the unsolicited adverse events were mild and resolved without intervention. Among children in part A of the study, no serious adverse events were observed during the 28-week trial period, except for one case of grade 4 leukocytosis that resolved without intervention and was considered to be unrelated to L9LS. In part B, local and systemic adverse events were uncommon and similar across the three treatment groups. All events were mild to moderate in severity and resolved without intervention.

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